tbuckley/cabot-search huggingface dataset:
Abstract 2072: Computational modeling of metabolic variations in tumor microenvironment
Authors: Tingbo Guo, Haiqi Zhu, Xiao Wang, Jia Wang, Xinyu Zhou, Yuhui Wei, Pengtao Dang, Chi Zhang, Sha Cao
Journal: Cancer Research (2023)

Abstract Dysregulation of metabolic pathways is a hallmark of cancer. Despite a plethora of knowledge on the core components of metabolic pathways we have gained, there are still major gaps in our understanding of the integrated behavior and metabolic heterogeneity of cells in the context of their microenvironment. Essentially, metabolic behavior can be determined by different factors and vary dramatically from cell to cell due to their high plasticity, driven by the need to cope with various dynamic metabolic requirements. Large amount of single-cell, spatial or tissue multi-omics data obtained from disease tissue has been proven to be endowed with the potential to deliver information on a cell functioning state and its underlying phenotypic switches.We have recently developed single-cell flux estimation analysis (scFEA) to predict sample-wise metabolic fluxome by using single-cell or bulk transcriptomics data. We further developed a web portal scFLUX.org, empowered by our scFEA method, expanding the analytic ability to both human and mouse metabolic networks. We also developed a probabilistic model named Michaelis-Menten-based Flux Estimation Analysis (mmFEA) for statistical inference of flux changes between conditions or cell types based on matched or unmatched gene expression data, metabolomics data, and partially observed kinetic parameters. These methods provide the following unmet capabilities to study metabolic variations in cancer: (1) reconstruction of cell or tissue specific and subcellular-resolution metabolic network, (2) estimation of cell-/sample-wise metabolic flux by considering metabolic imbalance, metabolic exchange between cells, and shifted redox, pH and energy balance in disease microenvironment, (3) a systematic evaluation of functional impact of variations in gene expression, genetic/epigenetic variations, metabolite availability and network structure on the context specific metabolic network and flux, (4) estimate the impact of each gene on flux by using a first-order derivative, (5) perturbation analysis to predict how alterations in enzymes or metabolites may affect the metabolic flux, and (6) identification of the samples and sub-network of a distinct metabolic shift.The methods were validated on matched scRNA-seq, metabolomics and fluxomics data. We demonstrated the function of this computational framework on pan-cancer transcriptomics and proteomics data, and single cell and spatial transcriptomics data. Citation Format: Tingbo Guo, Haiqi Zhu, Xiao Wang, Jia Wang, Xinyu Zhou, Yuhui Wei, Pengtao Dang, Chi Zhang, Sha Cao. Computational modeling of metabolic variations in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2072.
Abstract 2077: Spatial analyses methods for visualization and interrogation of tumor immune micro-environment using multiplexed images
Authors: Vidhya Kewale, Komal Das
Journal: Cancer Research (2023)

Abstract Immunotherapies are new and promising treatments but work only for a small subset of patients. IHC staining is the current standard technique for diagnosing and a commonly used research technique but only allows for evaluation of one, or maximum two, biomarkers at a time. Multiplexed immunofluorescence assays and multispectral imaging technology can label up to six biomarkers on the same tissue section to capture the tumor-immune tissue environment complexity at the single-cell level. These images are very data-rich, but the crowding of information on the tissue can make it difficult to derive meaning directly from the multiplexed images. Current commercial and open-source software has the capability to segment each cell and quantify each biomarker; however, there are not yet any computational tools to capture spatial relationships. With R programming, we developed a toolkit to quantify and visualize multiplexed imaging data for detailed quantification and spatial analysis. Using our computational toolkit, novel questions about the tissue behavior can be addressed, such as tissue heterogeneity, different cell types, cell functional status (naïve, exhausted, experienced, etc.), spatial visualization and quantification of expression level of biomarkers across the tissue, proximity and interaction of different cell types at the single cell level, and much more. We plan to release this toolkit as a web-based R-Shiny app to allow biologists and clinicians to upload their multiplexed imaging data and choose combinations of cell characteristics they would like to analyze. The power of multiplex imaging is the detailed spatial data it provides, and our data analytics methods can be used to effectively extract relevant information about single-cell level relationships. Citation Format: Vidhya Kewale, Komal Das. Spatial analyses methods for visualization and interrogation of tumor immune micro-environment using multiplexed images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2077.
Abstract PL05-02: To the tumor and beyond: Tales of a holistic miRNA delivery vehicle
Authors: Andrea L. Kasinski
Journal: Cancer Research (2023)

Abstract Like the challenges and skepticism that faced the antibody therapeutics field over a decade ago, RNA therapeutics is facing the same. And, like the antibody therapeutics field, we are beginning to realize the clinical impact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval of mRNA vaccines to prevent against SARS-CoV-2 and the first FDA approved RNAi drugs targeted to the liver. Unfortunately, RNA-based drugs targeted to cancer cells is lagging behind, even with countless years of work that has revealed the power of using RNAi for treating oncological diseases. Lack of success in this space is attributed to inability to deliver RNAi safely and effectively. A successful delivery agent requires multiple features. First, the agent must deliver the RNA specifically to the intended cells. Second, the agent must have a large therapeutic window, meaning that toxicity, if observed, should occur at doses that are orders of magnitude higher than the therapeutic dose. Third, if delivery of the RNA is by way of a specific ligand and receptor pair, as is the case herein, the RNA must successfully escape the endosome. Simply swelling the endosome is not enough if noncovalent interactions between the ligand and the receptor cannot be disrupted. Fourth, the RNA should include appropriate stabilizing modifications to increase intracellular half-life that will reduce dosing and cost. Through hard work and dedication in this space, we have come up with an inclusive, easily synthesized, intramolecular molecule that achieves all of these essential features. Moreover, the ligand used to achieve successful delivery is also being evaluated for imaging tumors localized in the central nervous system. Here, the challenges we face, the hurdles we have overcome, and the barriers that still remain to achieve success in revealing the clinical potential of miRNA as anti-cancer therapeutics will be presented. Citation Format: Andrea L. Kasinski. To the tumor and beyond: Tales of a holistic miRNA delivery vehicle. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr PL05-02.
Abstract 2365: Visualizing exosome structure in Dasatinib resistant colon cancer cells
Authors: Hui Min Koo, Yi-Wen Lu, Yu-Chi Tseng, Kai-Yu Tseng, Yen-Tse Lu, Wei-Ting Chao
Journal: Cancer Research (2023)

Abstract Cells release molecules through vesicles or into specific locations through exocytosis. Extracellular vesicle is divided into ectosomes and exosomes. Exosomes has been the main mechanism of discussion in recent studies and cancer research. As Exosomes with a diameter of ~30-160 nm (with an average diameter of 100 nm) carries intracellular molecules such as DNA, RNA, miRNA, proteins, and lipids. The physiological function of exosomes is not fully understood at present, it is important to understand the role of exosome in cancer. Src is highly activated in colon cancer and Src inhibition is the potential treatment strategy in colon cancer. In this study, colon cancer cells HT-29 were used to investigate the difference sizes of exosomes that response to Src inhibitor treatment. In the preliminary results, the exosome from HT-29 cultured medium were isolated and examined by transmission electron microscopy (TEM). The micrograph showed the average size of exosome is around 100 nm. When HT-29 were treated with Dasatinib (DST) the Src inhibitor, the drug resistant (DSTR) cells were grown, the secreted exosome from DSTR were collected and demonstrated the bigger size of exosome with average diameter of 130 nm. The role of the size changes of exosome in response to Dasatinib resistant will be further investigated, however, this study provides the clues that exosome detection can be applied in monitoring drug resistance. Citation Format: Hui Min Koo, Yi-Wen Lu, Yu-Chi Tseng, Kai-Yu Tseng, Yen-Tse Lu, Wei-Ting Chao. Visualizing exosome structure in Dasatinib resistant colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2365.
Abstract 1722: KRAS, BRAF, BRCA1 and EGFR mutation-specific panels using hydrogel-based 3D <i>in vitro</i> tumor models
Authors: Bin Xue, Julia Schüler, Christopher Harrod, Zoji Bomya, Kolin C. Hribar
Journal: Cancer Research (2023)

Abstract Mutation-targeting therapies have become a transformative technology and in many ways a new paradigm for cancer treatment for patients. The early development of Erlotinib for non-small cell lung cancer paved the way for EGFR treatment, irrespective of tumor indication subtype. And the more recent launch of Sotorasib for KRASG12C mutation has marked a turning point for the once undruggable mutation. The advent of gene specific-treatments requires a reconfiguration of preclinical models which more effectively represent the said mutation in populations of diverse backgrounds and tumor indications. 3D models which have the ability to recreate the key hallmarks of cancer - such as growth, invasion, immune infiltration and suppression, stromal transformation, drug diffusion, as well as gene mutational signatures - are of exceptional interest to drive rapid and scalable compound efficacy screening. Here, we developed four 3D in vitro tumor panels carrying mutations in one of the following genes - KRAS, EGFR, BRCA1, and BRAF - as well as wildtype models for comparison. The tumors were grown in a hydrogel matrix in 96-well plates with stromal fibroblasts and screened with the standard of care (e.g. Sotorasib for KRASG12C, Erlotinib for EGFRmut, the PARP inhibitor Olaparib for BRCAmut, and Vemurafenib for BRAFV600E) and other known therapeutic compounds that target their respective mutations. The utility of a 3D hydrogel matrix and fibroblasts in the panels’ models were key in recreating the stromal compartment of the tumor microenvironment. Endpoints were determined within four days of treatment, including tumor size reduction and tumor killing, via high-content image analysis. The Panels’ robustness as demonstrated by the reproducible results in independent experiments suggests they can be utilized at in vitro pharmacology stages and earlier in Hit and Lead finding screens. Citation Format: Bin Xue, Julia Schüler, Christopher Harrod, Zoji Bomya, Kolin C. Hribar. KRAS, BRAF, BRCA1 and EGFR mutation-specific panels using hydrogel-based 3D in vitro tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1722.
Abstract 5930: Single day workflow for high-quality whole genome analysis of thousands of single cells
Authors: Jay A. West, Jeff G. Blackinton, Kyle Hukari, Joe Dahl
Journal: Cancer Research (2023)

Abstract DNA sequencing technology provides the capability to tell the story of every cell in a heterogenous sample. ResolveDNA® generates uniform coverage of &amp;gt;95% of a single genome, enabling researchers to generate single-cell genomic data of unparalleled quality. Here, we report an enhancement to the ResolveDNA® workflow that increases the rate of data collection; the ability to reliably generate complete genomic information from up to 1536 cells in parallel from a single experiment. To achieve this, we have coupled a high-throughput automated process to a low volume reaction using the latest ResolveDNA® 2.5-hour chemistry. This establishes the potential for users to go from a single cell, or low-input DNA sample, to ready to sequence libraries in a single day for &amp;gt;3000 samples. As with earlier ResolveDNA® workflows, these reactions generate negligible amounts of contaminating and off target DNA during the reaction. A typical single-cell reaction yields ~ 85 ng of DNA. The single cell’s amplified DNA product is amenable to multiple post amplification library preparation processes. We utilized both BioSkryb ResolveDNA® and Watchmaker Library Preparation kits for Illumina sequencing. We did not identify significant differences in the performance of the two products. Libraries were assessed at a depth of ~ 2million reads and determined to be of high quality, with low rates of chimeric DNA formation and less than 1% mtDNA resulting in the reaction product. A subset of samples was probed at &amp;gt;200 million reads, with &amp;gt;85% of the genome covered at 1x. Consistent with earlier ResolveDNA® workflows, the libraries were characterized with &amp;gt;99% precision and &amp;gt;80% sensitivity. The story told from a single cell’s genome drives discovery and shines a light on the questions surrounding the causes of disease and cellular function. This workflow is designed to empower researchers to probe the genomic landscape of a heterogenous tissue sample. Citation Format: Jay A. West, Jeff G. Blackinton, Kyle Hukari, Joe Dahl. Single day workflow for high-quality whole genome analysis of thousands of single cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5930.
Abstract 5982: A potent and selective CDK8 inhibitor ABM-3249 with excellent efficacies in multiple in vivo cancer models
Authors: Chen Chen, Charles Huang, Min Xu, Xiuquan Chen, Xiaobing Lv, Chen Yang, Lanjiao Zhao, YouQin Chen, Jizhi Li, Li Zhao
Journal: Cancer Research (2023)

Abstract CDK8 is a member of the CDK family in which belongs to the serine/threonine protein kinase. It binds with cyclin C to regulate the transcription. By modulation of various gene expression programs, CDK8 associated with the mediator complex to sustain proliferation and viability of cancer cells. CDK8 has been identified as an important factor in cancer occurrence and development. It also involves in the regulation of cancer cell stress response to radiotherapy and chemotherapy, assists tumor cell invasion, metastasis and drug resistance. Therefore inhibition of CDK8 is regarded as a promising target for cancer therapy. ABM-3249 was discovered as a potent and selective CDK8 inhibitor with a novel chemical structure. It inhibited CDK8 kinase activity in biochemical assay and cellular binding assay, with IC50 values of 1.4 nM and 19nM respectively. ABM-3249 displayed good kinase selectivity: &amp;lt;50% inhibition on all other CDK family members at 1uM. Consistently, ABM-3249 reduced STAT1-S727 phosphorylation with an IC50 of less than 100nM. ABM-3249 showed good ADME properties with high oral bioavailability (~90%) in rodents. In efficacy studies, ABM-3249 exhibited excellent anti-tumor activities in multiple in vivo models. In an AML MV4-11 xenograft model at 25mpk oral dosing ABM-3249 achieved complete remission in all mice within 17 days and no tumor recurrence within one month after drug withdrawal. ABM-3249 showed good efficacies as a single agent, as well as a synergetic effect with anti-PD1 combination in a murine colon cancer MC38 model. It also showed an efficacy in a murine colon cancer B16F10 metastasis model. In addition, ABM-3249 displayed a good safety margin in a preliminary tox screen in rodents. Citation Format: Chen Chen, Charles Huang, Min Xu, Xiuquan Chen, Xiaobing Lv, Chen Yang, Lanjiao Zhao, YouQin Chen, Jizhi Li, Li Zhao. A potent and selective CDK8 inhibitor ABM-3249 with excellent efficacies in multiple in vivo cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5982.
Abstract 594: Effects of interstitial pressure on lung cancer cells
Authors: Shinsaku Tokuda, Keisuke Onoi, Tadaaki Yamada, Koichi Takayama
Journal: Cancer Research (2023)

Abstract Chronic inflammation is a risk factor for various types of cancer. The pressure in the interstitial tissues has been reported to be elevated in chronic inflammation and cancer. However, little is known about the biological effect of pressure from the basal side on epithelia, and a significance of the elevated interstitial fluid pressure in cancer biology is still poorly understood. In this study, we investigated the effect of hydrostatic pressure on cultured lung cancer cells grown on Transwell permeable filters by changing the height of the surfaces of culture medium in the apical and basal sides. A gradient of the hydrostatic pressure from the basal to the apical side induced stratification of epithelia. The elimination of the hydrostatic pressure gradient restored the stratification of epithelia. Interestingly, cavities were found within the stratified epithelia, and the characteristics of apical cell polarity including microvilli and tight junctions were formed in the surfaces the cavities. The cavities with similar aberrant cell polarity were also observed in human lung cancer tissues. The hydrostatic pressure gradient from the basal side also promoted cell proliferation and suppressed apoptosis. On the other hand, the expression levels of phosphorylated ERK and AKT were not significantly affected by the hydrostatic pressure. These results indicate that the pressure from the basal side to the epithelia promotes cell proliferation, suppresses apoptosis and induces aberrant cell polarity, which results in epithelial stratification. The findings in this study suggest that the elevated interstitial fluid pressure in chronic inflammation and cancer tissues facilitates cancer growth and plays a significant role in cancer biology. Citation Format: Shinsaku Tokuda, Keisuke Onoi, Tadaaki Yamada, Koichi Takayama. Effects of interstitial pressure on lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 594.
Abstract 324: Nickel exposure alters extracellular vesicles biogenesis to carry NUPR1 and mediate cancer progression
Authors: Shan Liu, Angelica Ortiz, Juan Iovanna, Max Costa
Journal: Cancer Research (2023)

Abstract Nickel (Ni), a group I human carcinogen by the International Agency for Research on Cancer (IARC) alters expression of various oncogenic molecules in cells resulting in adoption of cancer cell phenotypes, such as anchorage-independent growth, migration, and invasion. Cancer cell phenotypes are altered by internal genetic or epigenetic changes or in response to external signals mediated by soluble proteins or extracellular vesicles. However, few studies have linked extracellular vesicles (EVs) in response to environmental pollutants, such as Ni. Nuclear Protein 1 (NUPR1) is a stress response protein that is upregulated in cancer cells and it is also upregulated in cells following chronic Ni exposure. However, the role of NUPR1 in EV biogenesis or EV-mediated cancer progression is unknown. To explore the potential role of EVs in Ni-induced cancer progression, this study examined the effect of Ni-exposure on EV signature. Sizes and concentration of EVs from BEAS-2B cells, 6 weeks-Ni-treated BEAS-2B cells (Ni-6W) and Ni-transformed BEAS-2B cells (Ni-3) were identified by nanoparticle-tracking analysis (NTA) and transmission electron microscopy (TEM). In the results, showed that Ni-6W and Ni-3 released more EVs compared to the control. The transcription expression levels of EVs biogenesis markers, CD63, CD82 and Flotillin-1 (FLOT) were coincidentally increased in Ni-6W and Ni-3 compared to the BEAS-2B. We further identified that inhibition of NUPR1 by using the shRNA or NUPR1 inhibitor ZZW-130 can rescue the increased releasing of EVs induced by Ni exposure. Here we demonstrated that Ni exposure elevated EV release and that these Ni-altered EVs contributed to a pro-inflammatory environment associated with tumorigenesis and cancer progression. Moreover, we provided a new method of regulating EVs biogenesis by targeting NUPR1, this would be crucial for EV-based cancer therapy. Citation Format: Shan Liu, Angelica Ortiz, Juan Iovanna, Max Costa. Nickel exposure alters extracellular vesicles biogenesis to carry NUPR1 and mediate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 324.